Bioresorbable material and method for producing the same

ABSTRACT

A synthetic material is disclosed, which is constituted by a copolymer of D, L-lactide and ε-caprolactone (which itself is characterized by lower degradation times than those obtainable with copolymers of L-lactic acid and ε-caprolactone), obtained by using as reaction control agent a sugar dianhyide with non-toxic characteristics. The use of suar dianhydrde in the reaction has a considerable control effect on the molecular weight of the copolymer and, thanks to its low molecular weight, this copolymer is characterized by extreraely short resorption times, in the order for the example of one or two months. The copolymer is used as covering clement to be placed around tendon sutures and/or nerve tracts with the aim of preventing formation of scarry adherences between the suture lines and the soft surrounding tissues.

This is a 371 of PCT/IT96/00193 filed Oct. 21, 1996.

TECHNICAL FIELD

The invention relates to a method for obtaining an absorbable orbioresorbable material for use as a covering element in preventing scaradherences.

More in detail, the present invention relates to a method for obtaininga material, provided with relatively short absorption times for thehuman body, for use as a covering element in a zone where scaradherences might develop, for example in the area around a sutureperformed on a tendon and/or a nerve tract, as well as internally of thespinal foramen after spinal surgery.

The invention further relates both to the material obtained by themethod and to a cladding element for prevention of adherences realisedwith said material.

The invention finds its principal application in the medical-surgicalfield.

BACKGROUND ART

The most frequent complication consequent to surgical reconstruction ofa tendon and/or a traumatically severed nervous tract is constituted bythe formation of scar tissue adherences of the tendon suture line (or ofthe suture lines of the single nerves belonging to a bundle), with thesurrounding soft tissues or the bone surface adjacent to the suturedlesion.

These adherences, which can occur independently of the surgicaltechnique employed in repairing the lesion, can to a considerable degreelimit the tendon sliding function, so much so that it is common practiceto follow a first surgical operation with a second remedial operation,once the tendon has re-established its biological continuity, to improvetendon excursion: this is particularly common in the field of handsurgery with regard to the flexor apparatus of the hand.

Further, following spinal surgery operations, once the spinal foramenhas been opened to afford access to the discs or nervous structures ofthe rachis, scar tissue forms almost constantly between theosteo-articular surfaces, the muscles around the vertebrae, theendocranial sac and the nerve roots, which limit the small movement thatthe nerve roots make inside the connecting foramen in order to adapt tothe various positions assumed by the spinal column. This movementlimitation can lead to painful clinical symptoms which might even beworse than those presented pre-operation and at the origin of the wholeintervention.

To obviate the above-mentioned problem, apart from renderinginterventions as non-invasive as possible, a practice often employed isthat of isolating the nervous structures with free strands of fattytissue removed from the sottocutaneous area; absorption of the fattytissue is not, however controllable, and manipulation of same presentssome difficulties.

In the field of regeneration of single lacerated nerves, use is made ofgenerally tubular elements acting as guides for the two extremities of anerve during the regeneration period thereof.

In this context, use is made of nerve guides constituted bynon-biodegradable and bioresorbable materials, such as for examplesilicone rubber (G. Lundborg et al., Exp Neurol. 76 (1982) 361, G.Lundborg et al., Scand. J. Plastic Reconstructive Hand-Surgery 25(1991)79, G. Lundborg et al. J Neuropathol Exp. Neurol. 41 (1982) 412, M.Merle et al., Microsurg. 10 (1989) 130, B. R. Seckel et al. PlasticReconstructive Surg. 78 (1986) 793), Acrylic Polymers (B. G. Uzman andG. M. Villegas, J. Neurosci. Res. 9(1993)157), polyethylene (P. G.Cordeiro et al., Plastic Reconstructive Surg. 83 (1989) 1013) elastomerhydrogel (R. D. Keeley et al., J. Reconstructive Microsurg. 7(1991) (2)93) or porous stainless steel (W. E. Kuhn and J. L. Hall in “ModernDevelopments in Powder Metallurgy”, edited by H. H. Hausener and P. W.Taubenblat, American Powder Metallurgy Institute, Princeton N.J. p.279).

The nerve guides, which are synthesised in a non-biodegradable materialthat remains in situ as a foreign body, can limit the regenerativefunction of the nerve and give rise to irritation, sometimes years afterimplantation, in some cases so serious as to necessitate a furtheroperation to remove them.

Also known, in the field of specific application as nerve guides, is theuse of biodegradable and bioresorbable material in a predetermined timeperiod, in general comprised between six months and two years.

For example, the prior art teaches use of a copolymer derived fromL-lactide combined with poly-ε-caprolactone (W. F. A. Den Dunnen et al.in “A new PLLA/PCL copolymer for nerve regeneration”, Journal ofMaterials Science Materials in Medicine 4 (1993) 521-525), G. Perego etal. in “Preparation of a new nerve guide, from apoly(L-lactide-co-6-caprolactone)”, Biomaterials 1994, Vol 15 no. 3,189-193); with like aims an ester of hyaluronic acid (Favaro et al. in“Peripheral Nerve Regeneration Through a Novel Bioresorbable NerveGuide”, ASAIO Transactions 1990 36 (3), M291-M294).

All of the above-mentioned materials have good non-toxic characteristicsand low rejection reactions; reabsorption times are relatively long,generally over six months, for which reason these materials are notsuitable for other applications requiring much shorter reabsorptiontimes, for example one month.

“An Experimental Study on an Adhesions-Blocking Membrane in the FlexorTendon of Chicken-Part”, Clinical materials 6(1) 1-12 (1990) proposedthe use of a membrane realised with a copolymer of leucine-polyeurethaneblocks, derived from poly(tetra glycol methylene), toluene diisocyanateand hydrazine.

Copolymers containing 70% leucine were biodegradable in vivo (rat) inabout six months, differently to those containing leucine 50%, whichwere non-biodegradable. From the published data it may be derived thatan increase in leucine concentration leads to lower material elasticityand permeability.

For research into adherence inhibition in tendon regeneration it wouldseem that the 70% leucine composition was chosen as it offered areasonable compromise between the needs for elasticity, permeability andbiodegradability.

It must be remembered however that this material can generate, duringdegradation, an aromatic amine (toluene diamine), whose toxicity cannotbe ignored.

Document U.S. Pat. No. 5350573 describes a method and composition forpreventing adhesions during surgical operations. The surface of thetissues and the surgical instruments involved in the operation arecovered with a solution of a water-wettable polymer before contactingtissue duringthe operation. The composition comprises a solution ofpolymer material having a molecular weight of 500000 or above with aweight concentration comprised between 0.01 and about 15%.

Finally, document U.S. Pat. No. 5358973 describes a composition whichcan be used in surgical operations with the aim of preventing adhesionsbetween tissue surfaces, said composition being an aqueous solutioncontaining dextran and hyaluronic acid.

DESCRIPTION OF THE INVENTION

The present invention provides a method for obtaining a new resorbablematerial, characterised by extremely brief resorption times, in theorder of one or two months, and thus indicated for use as a covering forprevention of adherences, for example tendon sutures and/or nervetracts, with healing times as indicated above.

This is obtained by carrying out a method having low resorption times,and comprising a copolymersation reaction of D, L-lactide ande-caprolactone, characteted in that a synthesisation is performed usinga reaction control agent a sugar dianhydride.

Especially advantageous forms of embodiment of the method according tothe invention are characterised by the following The said sugardianhydride is constituted by 1,4:3,6-dianhydride-(D)-sorbitol or by1,4: 3,6-dianhydride-(D)-mannitol. Specifically, the1,4:3,6-dianhydride-(D)-sorbitol is used at a concentration comprisedbetween 0.30% and 0.60%, advantageously 0.44%. Further, thecopolymersation reaction is carried out with a presence of a specialcatalyst; and said catalyst is preferably constituted by tin octanoate.Thus, the sugar dianhydride can be 1,4:3,6-dianhydride-(D)-sorbitol or1,4:3,6-dianhydride-(D)-mannitol.

The invention also relates to a material obtained using the method ofthe invention, The resorbable material is for use as a cladding elementfor prevention of scar adherences between surfaces of tissues subsequentto surgical operations thereon and is characterised in tat said materialis constituted by a copolymer of D, L-lactide and ε-caprolactone havinga molecular weight which is tower than 1 dl/g.

Especially advantageous forms of embodiment of the material according tothe invention are that it has a moleculear weight which is about 0.59dl/g and it is resorbable over a period of time comprised between aboutone and two months.

Finally, the invention provides an element made of resorbable materialwhich can be used as a covering for prevention of adherences, forexample in tendon sutures and/or nerve tracts,

This covering element is for prevention of scar adherences betweentissue surfaces subsequent to surgical operation, and is characterisedin that it is constituted by a material as described above. The coveringelement is used for prevention of scar adherences between tissuesurfaces subsequent to operations for surgical reparation on tendonsand/or nerve tracts, as well as for spinal surgery internally of thespinal foramen. The element exhibits a tubular or a flat shape.

This element is described in claims from 10 to 12.

The synthetic material according to the invention is constituted by acopolymer of D,L-lactide and ε-caprolactone (which itself ischaracterised by lower degradation times than those obtainable withcopolymers of L-lactic acid and ε-caprolactone), obtained by using asreaction control agent a sugar dianhydride with non-toxiccharacteristics, and thus suitable for the purposes of the invention.

Experiments carried out by the applicant have surprisingly revealed thatthe use of sugar dianhydride as a control agent resulted in a copolymerwith very low inherent viscosity (thus having a low molecular weight),in the example much lower than viscosities of similar copolymersobtained without the use of sugar dianhydride.

Therefore the use of sugar dianhydride in the reaction has aconsiderable control effect on the molecular weight of the copolymerand, thanks to its low molecular weight, this copolymer is characterisedby extremely short resorption times, in the order for example of one ortwo months.

Such resorption times are decidedly lower than those obtained usingknown-type similar materials, and can be compared to those obtained bymeans of other biomaterials, such as hyaluronic acid, modified or not,which does not have the often-advantageous chemical-physical andmechanical properties of aliphatic polyesters, such as lactic acidcopolymers.

Therefore the material according to the invention is advantageousinasmuch as it is constituted by homo- and copolymers of lactic acidwith controlled molecular weight, with the help of a non-toxic agent forcontrol of the reaction.

According to a form of embodiment of the invention, the copolymer oflactic acid was obtained by synthesising D,L-lactide and ε-caprolactonein the presence of tin octanoate as catalyst and using1,4:3,6-dianhydride-(D)-sorbitol at 0.44% concentration.

More precisely, L-lactide was synthesised from D,L-lactic acid at 90%(Fluka, Buchs, CH); 1000 ml of D,L-lactic acid were placed in atwo-litre two-neck flask, and heated gradually to 200° C.,contemporaneously distilling the water formed by the reaction.

The viscous product thus obtained was depolymerised in the presence of atin powder catalyst, at a temperature of 200° C. and 0.1 Torr,contemporaneously distilling the D,L-lactide formed by the reaction.

The raw lactide thus obtained was recrystallised three times by methylisobutyl ketone, obtaining thus 385 g of white crystalline product,having a fusion temperature of 124-126° C.

The preparation was completed with a final drying stage at 45° C. and0.1 Torr for 24 hours.

Subsequently the ε-caprolactone (Fluka) was dried on CaCl₂ distilled atreduced pressure and conserved in nitrogen.

The 1,4:3,6-dianhydride-D-sorbitol (Fluka) was recrystallised usingethyl acetate, dried at 45° C. and 0.1 Torr for 24 hours, and conservedin nitrogen.

The tin octanoate (Sigma) was conserved in nitrogen on activatedmolecular sieves and used without further purification treatment. Thecopolymerisation was carried out in a nitrogen atmosphere in a 100 mltwo-neck flask, in which 118.89 g of D,L-lactide, 50.95 g ofε-caprolactone equal to 47.4 ml, 0.743 g of1.4:3,6-dianhydride-D-sorbitol and 0.100 g of tin octanoate were locatedin dry-box conditions.

The copolymerisation reaction was protracted for 7 hours at atemperature of 150° C., whereafter the flask was left to return toatmospheric temperature.

The material was rubbery and transparent.

The copolymer obtained in this way exhibits an inherent viscosity of0.59 dl/g, measured in chloroform at 25° C., considerably lower than theviscosity values (generally comprised between 2.5 and 3.5 dl/g) normallyobtained for the same copolymer in the absence of molecular weightcontrol agents.

A material having low resorption times, in the order of one or twomonths, is well adapted to use in setting up a surgical method forcovering tendon sutures and/or nerve tracts with the aim of preventingformation of scarry adherences between the suture lines and the softsurrounding tissues.

To this end, the suture zone is enveloped in a covering element made ofa material having a low resorption time, which isolates the suturedsegment from the surrounding tissues for a period of time which islimited to the completion of the healing processes.

The covering element can be constituted by a sheet of resorbablematerial, cell-proof, or by a tubular element internally of which anextremity of the operable tendon or nerve tract is inserted beforesurgical intervention, and which is arranged above the suture zone afterthe operation for connecting the ends of the tendon and/or the nervetract.

Experiments carried out by the applicant have demonstrated that alow-resorption time material, such as for example the copolymer oflactic acid obtained with the sugar dianhydride control agent of theinvention can advantageously be used in carrying out a method such asthe one described above.

The covering element made from low-resorption times material has in factbeen shown to be non-toxic, non-interacting with the healing processes,and resorbable in a considerably shorter time than that needed by alike-composed material obtained without the control agent.

For example, the applicant carried out an in vivo experimental study onan animal. The experiment was on chicken deep digital flexor. Chickenwas chosen as best for the purpose, because:

it has a digital flexor apparatus which anatomically similar to Human,and the sizes are suitable for surgical treatment;

the biological processes consequent to surgical lesion and healing areknown and sufficiently close to those of Human;

a valid flexion response can be obtained from mechanical stimulation ofChicken (by applying the palm of the claw to a cylindrical bar ofsuitable dimensions and rotating the bar, causing a constant prehensileresponse with powerful digit flexion), so that the possible flexionrange could be measured.

The study was carried out on three groups of animals.

The first group was used to evaluate the biological aspects of tendonrepair in an isolated environment. It was constituted by five animals,who were subjected under general anaesthetic to traumatic lesion of theflexor apparatus of the second digit of each claw. The wound waspalm-transversal throughout, interesting the skin, subcutaneous level,flexor tendons up to the bone of the median phalanx.

Subsequently the animals were operated, with a longitudinal lateralincision of the digit and raising of the palm cutaneous flap, avulsionof the surface flexor tendon up to bone insertion, repairing of the deepflexor by modified Bunnell technique with single thread suture Prolene4-0, and covering of the tendon in a tube of material according to theinvention, extending by 1 cm proximally and distally of the tendonsuture line.

The claws were immobilised in a plaster-of-paris cast with the operatedclaw arranged in a three-quarters of total flexion excursion.

The animals were sacrificed respectively at 1, 2, 3, 4 and 6 weeks afterthe operation, the claws amputated and the regions operated subjected toa histological study to evaluate the extent of biological reparation inthe various phases, as well as to check for presence and characteristicsof any scar adherences around the tendon.

The findings could then be compared with those relating to the numerousexisting studies on tendon lesion healing in the absence of interplacedmaterial.

The second and the third groups were respectively constituted by fiveanimals each.

The animals were subjected to trauma and surgical treatment similar tothat of the first group, with the difference that for the animals of thesecond group no interposing material was used.

The animals of the two groups were thus healed, and the cast removedfive weeks after the operation, and the flexion capacity of the operateddigit evaluated using the above-described method of the cylindrical barimmediately after removal of the cast and in the two following weeks.

Digital flexion of the two groups was compared to evaluate the degree ofusefulness of the material according to the invention.

From the experiments it was found that there is a total absence-ofadherences and an almost total resorption of the material of theinvention.

The invention has been described herein with reference to some preferredembodiments thereof.

However, it is clear that the invention is not absolutely limited to theabove-described embodiments, and that it comprises numerous variationswhich belong in the scope of the invention, specifically with regard tothe composition of the low-resorption-times materials.

Low resorption times materials, both in lactic acid copolymer form as inthe above-described material, and in other types of aliphatic polyesterwith especially short resorption times, such as for example copolymersderived from glycol and ε-caprolactone, that is, using glycolic acid inthe place of lactic acid, and derivatives of hyaluronic acid.

With regard to the covering element made using such a material, it isclear that it can be made both in a tubular shape and in a leaf whichcan be enveloped about the suture zone.

What is claimed is:
 1. A method for obtaining a resorbable materialhaving low resorption times, comprising a copolymerisation reaction ofD, L-lactide and ε-caprolactone using 1,4:3,6-dianhydride-(D)-sorbitolto control at least one parameter from the group consisting of theviscosity or molecular weight of the copolymer.
 2. A method as in claim1, wherein the 1,4:3,6-dianhydride-(D)-sorbitol is used at aconcentration between about 0.30% and about 0.60% by weight.
 3. A methodas in any one of the preceding claims, wherein the copolymerisationreaction is carried out with a presence of a tin catalyst.
 4. A methodas in claim 3 wherein the tin catalyst is tin octanoate.
 5. A method asclaimed in claim 2 wherein the concentration is about 0.44% by weight.6. A method for obtaining a resorbable material having low resorptiontimes, comprising a copolymerisation reaction of D, L-lactide andε-caprolactone, comprising using a sugar dianhydride as an agent tocontrol at least one parameter selected from the group consisting of theviscosity or molecular weight of the copolymer.
 7. A method forobtaining a resorbable material having low resorption times, comprisinga copolymerisation reaction of D, L-lactide and ε-caprolactone,comprising using a sugar dianhydride as &i agent to control, at leastone parameter selected from the group consisting of the viscosity ormolecular weight of the copolymer, characterised in that the sugardianhydride is selectively 1,4:3,6-dianhydride-(D)-sorbitol or1,4:3,6-dianhydride-(D)-mannitol.
 8. A method as in claim 7, wherein the1,4:3,6-dianhydride-(D)-sorbitol is used at a concentration betweenabout 0.30% and about 0.60% by weight.
 9. A method as in any one of theclaims 7 or 8, wherein the copolymerisation reaction is carried out witha presence of a tin catalyst.
 10. A method as in claim 9, wherein thetin catalyst is tin octanoate.